Incremental advances in understanding the genetics, epigenetics, and biochemistry of aging are gradually pushing the field forward. \u00a0In addition, there are occasional new ideas that have the potential for quantum advances that change the nature of the game. \u00a0Last week, there were two game-changers, originating from the US East and West coasts.<\/p>\n
<\/p>\n
Allowing People to Eat While They\u2019re Fasting<\/b><\/p>\n
I got my start in aging science in 1996, after reading an article on Caloric Restriction<\/a> by Richard Weindruch. \u00a0My first act as a researcher was to write a letter (USPS, not an email–this was 1996) to Weindruch and ask whether the timing or the kind of food mattered for life extension. \u201cNot at all,\u201d he answered, \u201ccalories are the bottom line. \u00a0Just make sure you get all necessary nutrients.\u201d<\/p>\n Weindruch was well-informed, and what he said was state-of-the-art science in 1996, but today we know better. \u00a0Restricting protein and restricting particular nutrients<\/a> have been shown to deliver some of the same benefits as a CR diet; and intermittent fasting<\/a> has been validated as a life extension program in rodents, with strong evidence that it will work in people, too. \u00a0It\u2019s a good thing, because sticking to a low-calorie diet is hard for most people. \u00a0Now Weindruch is approaching retirement and his compatriot Roy Walford<\/a> left us in 2004. \u00a0Valter Longo \u00a0has picked up the mantle of practical CR research where they left off.<\/p>\n As I have come to expect, Longo does his homework. \u00a0The new publication<\/a> is convincing because it combines theory and history with longevity studies in mice and yeast, and metabolic data from a new short-term trial in humans.<\/p>\n <\/p>\n The Diet<\/b><\/p>\n The FMD (fasting-mimicking diet) is ketogenic, with restricted protein and a high percentage of calories from fat. \u00a0\u201cDay 1 of the diet supplies 1,090 kcal (10% protein, 56% fat, 34% carbohydrate), days 2\u20135 are identical in formulation and provide 725 kcal (9% protein, 44% fat, 47% carbohydrate).\u201d \u00a0\u00a0The diet is predominantly fat. \u00a0The closest single food that approximates these macronutrient ratios is the avocado. \u00a0The diet approximates two avocados per day. \u00a0But you could construct the same macronutrient ratios using rice or apples and adding vegetable oil or small quantities of nuts. \u00a0I assume that green leafy vegetables could be added to the diet without changing its effect, while making it more palatable and filling and giving you a vehicle for the vegetable oil.<\/p>\n Here are three sample menus of my own construction (don\u2019t blame Longo), each designed to give you \u2153 of the FMD nutrients for Day 1 or \u00bd the nutrients for Days 2-5. Each recipe has about 360 calories. \u00a0While these recipes mirror the macronutrient content of the FMD, they don’t have the same micronutrients, and they generally have a lot\u00a0of extra leafy-green bulk (fiber). \u00a0My recipes haven’t been\u00a0studied in a clinical trial.<\/p>\n [UPDATE added 8\/1: \u00a0Link to list of recipes<\/a>, created with data from USDA nutritional database<\/a>, in cooperation with Enid Kassner.]<\/em><\/p><\/blockquote>\n Sample Meal One<\/i><\/b>:<\/b> Sample Meal Two<\/i><\/b>:<\/b> Sample Meal Three <\/i>(red cabbage salad)<\/b>:<\/b> Sample Meal Four <\/i>(gazpacho)<\/b>:<\/b> Spice to taste–the effect on calories and macronutrients is negligible. \u00a0Salt freely<\/a> and supplement with magnesium<\/a>.<\/p>\n <\/p>\n The Data, mice<\/b><\/p>\n Mice were put on the FMD for 4 days, twice per month, starting when they were already middle-aged (16 months for mice ~ 50 years for humans). \u00a0They lived 11% longer than control mice (median) though maximum life span was not increased. \u00a0\u00a0There was some indication that the mice were unable to tolerate the FMD intervals when they were really old, that it was triggering their death, and the experimental protocol was modified so that FMD intervals were stopped when the mice were 29 months old (the human equivalent of 90 years).<\/p>\n Test mice fully compensated for the lost calories when they were returned to ad libitum<\/i> feeding, but still they weighed less–same lean mass but less visceral fat. \u00a0FMD mice had improved cognitive performance, stronger immune systems, lower markers of inflammation, and lower fasting blood sugar. \u00a0When they died, it was less likely to be of lymphoma, which is what usually kills lab mice.<\/p>\n <\/p>\n The Data, humans<\/b><\/p>\n Humans were on the FMD diet 5 days out of each month, in a preliminary test that ran for three months. \u00a0Like the rodents, humans compensated for the lost calories when they returned to free eating, but still lost weight (not lean mass, but body fat).<\/p>\n Blood sugar and markers of inflammation were down; fasting insulin and IGF-1 were lower. \u00a0The article made no mention of HDL or LDL cholesterol. \u00a0Longer term trials with more criteria for metabolic health are planned.<\/p>\n In case you can\u2019t tell, I\u2019m really impressed with Longo\u2019s work. \u00a0I think he has advanced the practice of human nutrition in the last few years more than anything that has been done in decades.<\/p>\n <\/p>\n Legitimizing Research in Anti-Aging Medicine<\/b><\/p>\n We already have, incidentally, a great deal of information about the benefits of metformin<\/a> in people with Type 2 diabetes (T2D, or metabolic syndrome). \u00a0It has been the first-line drug for T2D for fifty years, and about 150 million people<\/a> are taking metformin worldwide. \u00a0The huge numbers have made it easy to collect data on other diseases. \u00a0People taking metformin have lower rates of cancer, heart disease and dementia than people taking other diabetic drugs. \u00a0It is tempting to conclude that metformin forestalls the diseases of old age generally, but rates of all these diseases are already elevated in people with T2D. \u00a0The new question being asked is whether metformin will offer benefits for people who don\u2019t have diabetes to begin with. \u00a0There is one Scottish study<\/a> reporting that cancer rates for diabetics taking metformin are depressed below the rate for non-diabetics who don\u2019t take metformin. \u00a0Now that\u2019s promising.<\/p>\n Nature<\/a> reported last week that FDA had scheduled a hearing on Wednesday past (6\/24) to consider a proposed drug trial for metformin as an anti-aging remedy. \u00a0The protocol would be to identify patients who have symptoms of one of three age-related disease: \u00a0cardiovascular disease, cancer and dementia. \u00a0People with T2D would be excluded by design. \u00a0Subjects would be prescribed metformin or a placebo, and the researchers would look for an effect on the other two<\/i> diseases. \u00a0This design is a clever compromise between bureaucratic requirements and clean experimental methodology. \u00a0The bureaucratic requirement is that people assigned to take the drug must already be diagnosed with a recognized disease. \u00a0But it is the potential of metformin to reduce risk of the diseases that the subjects do not have<\/i><\/b> that is the target question for the study.<\/p>\n Barzilai already has a small, ongoing trial for metformin and aging registered at ClinicalTrials.gov<\/a>. \u00a0Just 15 patients will be enrolled, and the plan is to look at their gene expression profiles to see if metformin has an anti-aging effect. \u00a0A growing number of researchers (including me) thinks that gene expression drives aging, and last year, Steve Horvath of UCLA published a protocol<\/a> for measuring physical age of the human body by combining epigenetic markers (methylation) from hundreds of different chromosome sites that empirically appear most sensitive to age. \u00a0They use the acronym MILES<\/b> for M<\/b>etformin I<\/b>n L<\/b>onge<\/b>vity S<\/b>tudy.<\/p>\n The new study is far more ambitious.<\/p>\n Plans call for the trial to enrol 3,000 people aged 70\u201380 years at roughly 15 centres around the United States. The trial will take 5\u20137 years and cost US$50 million, Barzilai estimates, although it does not yet have funding.<\/p><\/blockquote>\n That\u2019s $17,000 per patient, for a drug that costs pennies. \u00a0Certainly the cost will hold up this project, and monitoring patients for diseases that are already covered in their annual physicals. \u00a0Why does it need to be so expensive?<\/p>\n I have written to Barzilai about the Wednesday meeting with FDA and he would only say to watch for an article in next week’s\u00a0Science magazine.<\/p>\n <\/p>\n In the Larger Scheme\u2026<\/b><\/p>\n The shortcut to modest gains in longevity is to work with the body\u2019s adaptation to caloric restriction. \u00a0CR is known to work in many different animals, and is known to offer health benefits in humans, (although human longevity studies are probably completely impractical). \u00a0So the search is on for \u201cCR mimetics\u201d, drugs that will put the body into a calorie-deprived state without actually having to eat less. \u00a0Intermittent fasting, the Longo diet, and metformin all work on the same pathway as CR. \u00a0Some researchers believe resveratrol works on this same pathway, and even for rapamycin there is significant overlap with the CR mechanism.<\/p>\n It is understandable that researchers should be investing their time and pharmaceutical companies their money in this area, because this is where returns on investment are surest. \u00a0But the potential of this approach is limited to a few years of life extension, and layering metformin on CR on fasting on resveratrol on rapamycin will not add more years, just the same few years many times over. \u00a0As I have said in previous columns, there is immediate potential in telomerase activation, and longer term my highest priority would be to understand the epigenetic changes that come with age.<\/p>\n","protected":false},"excerpt":{"rendered":"
\n4 oz salad greens + 4 oz cucumber
\n1 tbsp vegetable oil
\n1 tbsp vinegar
\n\u00bd apple (~4 oz)
\n\u00bd oz almonds<\/p>\n
\n6 oz cauliflower
\n1.5 oz sesame tahini
\n1 oz lemon juice
\n4 oz blueberries<\/p>\n
\n4 oz shredded red cabbage
\n3 oz shredded carrots
\n\u00bd oz cilanthro
\n\u00bd (mushed) avocado (~3 oz)
\n1 tbsp lime juice
\n2 tbsp apple juice
\n\u00be oz walnuts
\ngarlic and mustard to taste<\/p>\n
\n12\u00a0oz\u00a0canned or fresh tomatoes
\n4\u00a0oz fresh onion
\n1 tsp olive oil
\n4 oz black olives
\n2\u00a0tbsp\u00a0vinegar
\n4 oz cucumber
\n3\u00a0oz snap peas
\nsalt, black pepper, cayenne
\n(Blend together, leaving it chunky or smooth to taste)<\/p>\n
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